Identification of Organ-Enriched Protein Biomarkers of Acute Liver Injury by Targeted Quantitative Proteomics of Blood in Acetaminophen- and Carbon-Tetrachloride-Treated Mouse Models and Acetaminophen Overdose Patients



Qin, S, Zhou, Y, Gray, L, Kusebauch, U, McEvoy, L ORCID: 0000-0002-2169-6735, Antoine, DJ, Hampson, L, Park, BK ORCID: 0000-0001-8384-824X, Campbell, DS, Caballero, J
et al (show 10 more authors) (2016) Identification of Organ-Enriched Protein Biomarkers of Acute Liver Injury by Targeted Quantitative Proteomics of Blood in Acetaminophen- and Carbon-Tetrachloride-Treated Mouse Models and Acetaminophen Overdose Patients. Journal of proteome research, 15 (10). 3724 - 3740.

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Abstract

Organ-enriched blood proteins, those produced primarily in one organ and secreted or exported to the blood, potentially afford a powerful and specific approach to assessing diseases in their cognate organs. In this paper, we demonstrate that quantification of organ-enriched proteins in the blood offers a new strategy to find biomarkers for diagnosis and assessment of drug-induced liver injury (and presumably the assessment of other liver diseases). We used selected reaction monitoring (SRM) mass spectrometry to quantify 81 liver-enriched proteins plus three aminotransferases (ALT1, AST1, and AST2) in plasma of C57BL/6J and NOD/ShiLtJ mice exposed to acetaminophen or carbon tetrachloride. Plasma concentrations of 49 liver-enriched proteins were perturbed significantly in response to liver injury induced by one or both toxins. We validated four of these toxin-responsive proteins (ALDOB, ASS1, BHMT and GLUD1) by Western blotting. By both assays, these four proteins constitute liver injury markers superior to currently employed markers such as ALT and AST. A similar approach was also successful in human serum where we had analyzed 66 liver-enriched proteins in acetaminophen overdose patients. Of these, 23 proteins were elevated in patients; 15 of 23 overlapped with the concentration-increased proteins in the mouse study. A combination of 5 human proteins, AGXT, ALDOB, CRP, FBP1, and MMP9, provides the best diagnostic performance to distinguish acetaminophen overdose patients from controls (sensitivity: 0.85, specificity: 0.84, accuracy: 85%). These five blood proteins are candidates for detecting acetaminophen-induced liver injury using next-generation diagnostic devices (e.g, microfluidic ELIZA assays).

Item Type: Article
Uncontrolled Keywords: Liver-enriched proteins, Selected reaction monitoring, Drug-induced liverinjury
Depositing User: Symplectic Admin
Date Deposited: 22 Nov 2016 08:52
Last Modified: 02 Sep 2022 07:16
DOI: 10.1021/acs.jproteome.6b00547
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3004636